# Titin in Skeletal Muscle Health and Disease

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2022 · $400,754

## Abstract

There is a rapidly increasing awareness of the importance of titin in causing neuromuscular disorders
(titinopathies), two of which we focus on in this work, centronuclear myopathy (CNM) and hereditary myopathy
with early respiratory failure (HMERF). Titinopathies frequently present early-onset muscle weakness and
respiratory difficulty but understanding their underlying mechanisms is held back by our still limited
understanding of the functional roles of titin in skeletal muscle. Titin comprises the third myofilament of muscle
and spans along the sarcomere, from Z-disk to M-band. Titin’s I-band region functions as a molecular spring
that generates passive stiffness with recent studies indicating that passive stiffness affects active force at sub-
maximal activation levels. However, it is not known how important titin’s stiffness is to overall skeletal muscle
health and if altered stiffness can cause a myopathy. That the importance might be high is suggested by our
pilot studies that reveal deranged titin stiffness and reduced active tensions in titinopathy patients with CNM.
Aims 1 and 2 address how altering titin-based stiffness affects both passive and active muscle properties and if
it can be disease-causing. We will perform mechanical studies on biopsies from titinopathy patients (focus on
CNM) as well as study two contrasting mouse models in which the stiffness of titin’s spring region is either
increased (PEVK truncation) or reduced (inactivation of Rbm20). The working hypothesis is that altering titin’s
spring region alters both passive muscle stiffness and active tension and that this causes myopathy. Aim 2
also studies a novel mouse model that mimics CNM with splice site mutations in titin’s spring region and we
will examine the functional consequences at the RNA, protein, structural and functional levels. We also study
the A-band segment of titin, specifically the C-zone. This zone has not been studied, it is clinically important as
this is where a large number of disease-causing mutations are found. We investigate in Aim 3 a mutation in
the C-zone exon 343 which causes HMERF, a myopathy with respiratory muscle involvement that can be
fatal. Using a novel HMERF mouse that we made the mechanistic basis of the disease will be studied.
Through excision of the mutated titin exon 343, the therapeutic potential of exon skipping for treating HMERF
will be tested. With its basic science and translational goals and its in-depth and integrative approach,
this application seeks to continue our track record of cutting-edge titin research. Powerful techniques and
novel mouse models are in place, pilot data support the guiding hypotheses, and our research team is
highly experienced. The proposal will greatly enhance insights in titin biology, titin’s role in muscle disease,
and titin’s potential as a therapeutic target.

## Key facts

- **NIH application ID:** 10468822
- **Project number:** 5R01AR073179-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Henk L. GRANZIER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,754
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468822

## Citation

> US National Institutes of Health, RePORTER application 10468822, Titin in Skeletal Muscle Health and Disease (5R01AR073179-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10468822. Licensed CC0.

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